Angiogenesis is the process of generating new capillary blood vessels from the pre-existing vasculature. After birth, angiogenesis contributes to organ growth, but in adulthood it is strictly regulated and occurs only during wound healing and in the female reproductive cycle. See Klagsbrun et al., Molecular angiogenesis. Chemistry & Biology 1999, 6 (8), R217-R224. Under normal physiological conditions, angiogenesis is tightly controlled by a series of pro-angiogenic and anti-angiogenic factors, which allow vascular growth for controlled periods of time. Ferrara, Vascular Endothelial Growth Factor as a Target for Anticancer Therapy. The Oncologist 2004, 9:2-10. Persistent, unregulated angiogenesis has been implicated in a wide range of diseases, including rheumatoid arthritis, macular degeneration, atherosclerosis, obesity, benign neoplasms, and cancers. See Moulton et al., Angiogenesis inhibitors endostatin or TNP-470 reduce intimal neovascularization and plaque growth in apolipoprotein E-deficient mice. Circulation 1999, 99, (13), 1726-1732; and Hanahan et al., The hallmarks of cancer. Cell 2000, 100, (1), 57-70. That these pathological states are unified by their status as “angiogenesis-dependent diseases” but are otherwise unrelated has led Folkman to propose the concept of angiogenesis as an “organizing principle” in biology, by which many types of seemingly dissimilar phenomena may be connected. See Folkman, Opinion-Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery 2007, 6(4):273-286.
A current principle focus of angiogenesis research concerns its role in cancer. Tumor growth depends heavily on neovascularization-tumors are marked by a state of constant hypoxia, and in order to grow beyond 1-2 mm in size they require new capillaries to supply nutrients, remove metabolic waste, and also to metastasize. See Hanahan et al., Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 1996, 86, (3), 353-364. Cancer cells begin to promote angiogenesis early in tumorigenesis; this “angiogenic switch” is marked by oncogene-driven expression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin 2 (ANGPT2), and platelet-derived growth factor (PDGF). Kerbel et al., Clinical translation of angiogenesis inhibitors. Nature Reviews Cancer 2002, 2, (10), 727-739. The best characterized pathway is that of VEGF and its receptors. VEGF has been shown to induce endothelial cell proliferation; furthermore, activation of the receptor VEGF2 has been associated with the production of matrix metalloproteinases (MMPs) which degrade the extracellular matrix (ECM), thus allowing migration of cells and further mobilizing pro-angiogenic proteins from the stroma. Ferrara, Vascular Endothelial Growth Factor as a Target for Anticancer Therapy. The Oncologist 2004, 9, 2-10; and Moses, The regulation of neovascularization by matrix metalloproteinases and their inhibitors. Stem Cells 1997, 15, (3), 180-189. Several of the pro-angiogenic proteins upregulate endothelial integrins and are thought to sustain endothelial cell viability during the detachments that are required as the cell migrates towards the tumor. Tumors also promote blood vessel growth by down-regulating endogenous angiogenesis inhibitors such as thrombospondin. Rastinej ad et al., Regulation of the activity of a new inhibitor of angiogenesis by a cancer suppressor gene. Cell 1989, 56, (3), 345-355.
Since Folkman first presented his hypothesis in 1971 that angiogenesis inhibitors could be used in the treatment of cancer, enormous effort has been directed toward the discovery and investigation of anti-angiogenic factors. The first to be identified was interferon-α/β in 1980, and over the past 27 years many more endogenous angiogenesis inhibitors have been isolated, thirty-three in the Folkman lab alone. See Folkman et al., Tumor angiogenesis—therapeutic implications. New England Journal of Medicine 1971, 285, (21), 1182-1186; and Folkman, J., Opinion—Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery 2007, 6, (4), 273-286. Extensive effort has also been expended to develop artificial angiogenesis inhibitors. These compounds are generally divided into two classes: direct and indirect inhibitors. Direct inhibitors of angiogenesis either neutralize VEGF in the blood plasma, such as the antibody Bevacizumab (AVASTIN) or prevent endothelial cell growth in response to VEGF or other angiogenic factor stimulation, such as the kinase inhibitor sunitinib malate (SUTENT). Indirect inhibitors, such as the small molecule gefitinib (IRESSA), block tumor cell production of VEGF or other pro-angiogenic factors. Direct angiogenesis inhibitors are less likely to induce acquired resistance because they target genetically stable endothelial cells instead of mutating tumor cells. Kerbel, Inhibition of tumor angiogenesis as a strategy to circumvent acquired-resistance to anticancer therapeutic agents. Bioessays 1991, 13, (1), 31-36.
Although when administered as single agents angiogenesis inhibitors have not provided long-term survival benefits, when given in combination with existing treatments these agents have shown utility in enhancing traditional chemotherapy or radiation therapy. Mayer, Two steps forward in the treatment of colorectal cancer. New England Journal of Medicine 2004, 350, (23), 2406-2408; Hurwitz et al., Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. New England Journal of Medicine 2004, 350, (23), 2335-2342; Teicher et al., Antiangiogenic agents can increase tumor oxygenation and response to radiation therapy. Radiation Oncology Investigations 1994, 2, (6), 269-276. It is known that tumor vasculature is “leaky”, being characterized by aberrant morphology, absent or loosely attached pericytes, an abnormal basement membrane, and high interstitial pressure. Jain, Normalizing tumor vasculature with anti-angiogenic therapy: A New Paradigm for Combination Therapy. Nature Medicine 2001, 7, (9), 987-989. Synergistic effects in combination therapy have been observed, supporting the predictions of Teicher that simultaneous targeting of both cancer cells and their supporting vasculature would provide maximal benefit. Jain, Normalizing tumor vasculature with anti-angiogenic therapy: A new paradigm for combination therapy. Nature Medicine 2001, 7, (9), 987-989. One current hypothesis is that the anti-angiogenic drug “normalizes” the tumor vasculature, decreasing leakage and allowing the chemotherapeutic agent more efficient access to the cancerous tissue. Teicher, A systems approach to cancer therapy (antiangiogenics plus standard cytotoxics, mechanism(s) of interaction). Cancer and Metastasis Reviews 1996, 15, (2), 247-272. Angiogenesis inhibition also decreases tumoral interstitial pressure, raising oxygen content in the tumor and increasing sensitivity to ionizing radiation. Teicher et al., Antiangiogenic agents can increase tumor oxygenation and response to radiation therapy. Radiation Oncology Investigations 1994, 2, (6), 269-276.
In addition to cancerous tissue, genotypically normal cells may also have tissue mass regulated by the endothelial microvasculature. Gerber et al., The role of VEGF in normal and neoplastic hematopoiesis. Journal of Molecular Medicine 2003, 81, (1), 20-31. Rats that have undergone hepatectomy to remove 70% of their liver regenerate the lost mass in approximately 10 days. If an angiogenic protein, such as VEGF, is administered systemically, the liver continues to grow beyond its normal size. In contrast, if an angiogenesis inhibitor is administered, liver regeneration is prevented; discontinuation of the inhibitor is followed by immediate liver regeneration. Folkman, Opinion-Angiogenesis: an organizing principle for drug discovery? Nature Reviews Drug Discovery 2007, 6, (4), 273-286; Greene et al., Urinary matrix metalloproteinases and their endogenous inhibitors predict hepatic regeneration after murine partial hepatectomy. Transplantation 2004, 78, (8), 1139-1144. Both bone growth and adipocyte enlargement are also under endothelial control, raising the possibility that in the future specific endothelial inhibitors may be used to control obesity and other tissue overgrowth. Street et al., Vascular endothelial growth factor stimulates bone repair by promoting angiogenesis and bone turnover. Proceedings of the National Academy of Sciences of the United States of America 2002, 99, (15), 9656-9661; Kolonin et al., Reversal of obesity by targeted ablation of adipose tissue. Nature Medicine 2004, 10, (6), 625-632.
Due to the fundamental role that angiogenesis plays in numerous pathological states, anti-angiogenic pharmaceutical agents have become targets of intensive research. Schenone et al., Antiangiogenic agents: an update on small molecule VEGFR inhibitors. Current Medicinal Chemistry 2007, 14, (23), 2495-2516. Currently, ten drugs that have an anti-angiogenic effect have been approved by the FDA, and 30 more are in Phase II or Phase III clinical trials. See Folkman, Opinion—Angiogenesis: an organizing principle for drug discovery?Nature Reviews Drug Discovery 2007, 6, (4), 273-286. Furthermore, drugs that have gained approval for the treatment of cancer are also being evaluated for the treatment of other angiogenesis-dependent diseases. In 2006, Ranibizumab, a fragment of the monoclonal antibody therapy Bevacizumab (approved in 2004 for colorectal cancer), was approved for direct injection into the eye to treat age-related macular degeneration. Ranieri et al., Vascular endothelial growth factor (VEGF) as a target of bevacizumab in cancer: From the biology to the clinic. Current Medicinal Chemistry 2006, 13, (16), 1845-1857. There is certainly a need for additional innovation in the field; angiogenesis is a highly complex process regulated by a host of factors, and it is believed that inhibition of multiple factors in combination may lead to enhanced patient outcome. See Folkman, Antiangiogenesis in cancer therapy—endostatin and its mechanisms of action. Experimental Cell Research 2006, 312, (5), 594-607. Furthermore, several of the currently available drugs are biologics and suffer the drawbacks of high production costs and required parenteral administration.